Autotaxin (ATX) is an autocrine motility-stimulating factor and an extracellular enzyme that catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). Although ATX can also hydrolyze sphingosylphosphorylcholine (SPC) to sphingosine-1-phosphate (S1P), the major source of extracellular S1P originates from the intracellular phosphorylation of sphingosine by sphingosine kinases (SphKs). LPA and S1P are well-characterized bioactive lysophospholipid mediators, which have critical roles in multiple cellular processes through binding and activating GPCRs. These two lipids have been implicated in various physiological (eg, cell growth, differentiation, migration and survival) and pathological (eg, angiogenesis, metastasis and autoimmunity) processes. The roles of LPA and S1P in autoimmune diseases, including rheumatoid arthritis (RA), have recently emerged. This review discusses recent findings suggesting that the LPA- and S1P-induced cellular functions of synoviocytes from patients with RA may contribute to the pathophysiology of the disease by exacerbating the disease process. ATX and the lysophospholipid mediators are potential targets for the treatment of patients with RA.